Polymer solutions

ABSTRACT

Copolymers of zwitterionic monomer, especially 2-methacryloyloxyethyl-2′-trimethylammoniumethyl phosphate inner salt, and hydrophobic comonomer, especially dodecylmethacrylate, are made in a monomer starved polymerization process in which solutions of monomers are fed to the reaction vessel in which initiator is present over an extended period. The copolymers have improved compositional uniformity and provide better coatings on a range of substrates. The novel copolymers can be distinguished from prior art batch type bulk solution polymerization polymers of the same monomer composition by solubility characteristics especially in alcohol/water mixtures. Particularly preferred coating compositions comprise an alcohol:water mixture containing around 20 to 40% by volume alcohol.

The present invention relates to biocompatibilising zwitterionicpolymers of improved solubility, processes for synthesising them,coating solutions and coating processes. The polymers are formed fromethylenically unsaturated monomers including a zwitterionic monomer anda hydrophobic monomer.

In WO-A-93/01221 we describe coating polymers formed from ethylenicallyunsaturated monomers including2-methacryloyloxyethyl-2′-trimethylammoniumethyl phosphate inner salt(HEMA-PC), and a surface binding monomer for coating substrates toimprove their biocompatibility, especially haemocompatibility. Surfacebinding monomers include hydrophobic monomers suitable for binding tohydrophobic surfaces. One such monomer copolymerisable with HEMA-PC islauryl methacrylate (n-dodecylmethacrylate). Examples of copolymersinclude 1:2 and 1:3 copolymers of HEMA-PC and dodecylmethacrylate.

Such copolymers are synthesised by a batch-type (one-pot) bulk solutionpolymerisation technique, in which the monomers are dissolved in asolvent system which is a solvent for both the monomers and for thepolymer. The polymerisaton solvent system is, for instance,methanol/tetrahydrofuran (5:9), or propan-2-ol ethylacetate (17:43volume or 1:1 volume). The polymerisation is initiated after all themonomers are dissolved in the reaction vessel. The polymer is recoveredby precipitation from acetone. The polymer is dissolved to form acoating composition, the solvent for the coating composition being, forinstance, ethanol/chloroform or propan-2-ol (isopropanol, (IPA)).

For some substrates, the solutions described in that earlierspecification result in uneven coatings. We have also found anotherproblem that the use of certain solvent systems for the coatingcompositions may adversely effect certain substrates. For instance, theuse of chlorinated alkanes may have a deleterious effect on theunderlying substrate on many substrates, eg membranes and other, poroussubstrates. Even the use of alcohols may have undesirable effects onsome substrates such as porous substrates or substrates which swell inalcohol.

In WO-A-98122516 we describe terpolymers of HEMA-PC, dodecylmethacrylate(or other hydrophobic comonomer) and a cationic comonomer. Thepolymerisation process was carried out by two different techniques. Onetechnique used a similar process to that described in WO-A-93/01221, inwhich a bulk solution polymerisation was carried out in a solventsystem, all of the monomers being included in the reaction vessel at thestart of the polymerisation process (the one-pot method). In the secondmethod, a polymerisation solvent comprising n-propanol in a reactionvessel was heated. To the heated solvent was added, drop wise, a coldmixed solution of the monomers in n-propanol and initiator. After allthe monomer had been added, additional initiator was added and thevessel maintained at the raised temperature for a further period oftime. The polymer was recovered by evaporation of the solvent,dissolution in a mixture of dichloromethane and methanol followed byprecipitation in acetone. This process was termed the monomer feedprocess.

In a new polymerisation process according to the invention,ethylenically unsaturated monomers consisting substantially only of:

-   -   a) 1 part by mole zwitterionic mono mer of the general formula I    -    in which        -   n is 2 to 24;        -   m is 0 to 20;        -   of the groups R¹, one may be methyl or hydrogen and the rest            are all hydrogen; and        -   X is a zwitterionic group; and    -   b) 1 to 10 parts by mole hydrophobic comonomer of the general        formula II        in which    -   p is 1 to 24,    -   are copolymerised in solution in a solvent system in which the        monomer mixture and the polymer are soluble, in which process        the monomers dissolved in a monomer solvent are fed constantly        over a monomer feed phase into a reaction vessel containing        solvent comprised in the said solvent system and radical        initiator under conditions at which polymerisation takes place,        at a predetermined monomer feed rate whereby the molar ratio of        zwitterionic monomer to hydrophobic comonomer in the reaction        vessel is maintained substantially constant (±10%) throughout        the monomer feed phase.

The zwitterionic monomer of the formula I is extremely hydrophilic. Ifthe chain between the methacyloyloxy group and the zwitterionic group Xcontains (oligo)alkyleneoxy moieties, that is m is other than 0, it ispreferred that the groups R¹ are all hydrogen. In such compounds, m ispreferably in the range 1 to 10, most preferably 1 to 5. It is, however,preferred that m is 0. Furthermore it is preferred that n is 6 or less,most preferably 4 or 3 or, most usefully, 2.

The process is of particular utility where the hydrophobic comonomer ishighly hydrophobic. The value of p is preferably at least 4, morepreferably at least 6, for instance up to 18, most preferably in therange 8 to 16, for instance 12. Although the group C_(p)H_(2p+1) may bea branched alkyl, it is preferred that it is a straight chain alkylgroup of the formula (CH₂)_(p)H.

In the zwitterionic monomer the general formula I, the zwitterionicgroup X preferably has the general formula III

-   -   in which the moieties A² and A³, which are the same or        different, are —O—, —S—, —NH— or a valence bond, preferably —O—,        and W⁺ is a group comprising an ammonium, phosphonium or        sulphonium cationic group and a group linking the anionic and        cationic moieties which is preferably a C₁₋₁₂-alkanediyl group,    -   preferably in which W⁺ is a group of formula        —W¹—N⁺R² ₃, —W¹—P⁺R³ ₃, —W¹—S⁺R³ ₂ or —W¹-Het⁺ in which:    -   W¹ is alkanediyl of 1 or more, preferably 2-6 carbon atoms        optionally containing one or more ethylenically unsaturated        double or triple bonds, disubstituted-aryl (arylene), alkylene        arylene, arylene alkylene, or alkylene aryl alkylene,        cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or        alkylene cycloalkyl alkylene, which group W¹ optionally contains        one or more fluorine substituents and/or one or more functional        groups; and    -   either the groups R² are the same or different and each is        hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or        aryl, such as phenyl, or two of the groups R² together with the        nitrogen atom to which they are attached form an aliphatic        heterocyclic ring containing from 5 to 7 atoms, or the three        groups R² together with the nitrogen atom to which they are        attached form a fused ring structure containing from 5 to 7        atoms in each ring, and optionally one or more of the groups R²        is substituted by a hydrophilic functional group, and    -   the groups R³ are the same or different and each is R² or a        group OR², where R² is as defined above; or    -   Het is an aromatic nitrogen-, phosphorus- or sulphur-,        preferably nitrogen-, containing ring, for example pyridine.

Most preferably, the zwitterionic group of the formula III, has thegeneral formula IV:

where the groups R⁴ are the same or different and each is hydrogen orC₁₋₄ alkyl, and q is from 1 to 4, in which preferably the groups R⁴ arethe same preferably methyl.

Alternatively, the zwitterionic group may be a betaine group (ie inwhich the cation is closer to the backbone), for instance a sulpho-,carboxy- or phospho-betaine. A betaine group should have no overallcharge and is preferably therefore a carboxy- or sulpho-betaine. If itis a phosphobetaine the phosphate terminal group must be a diester,i.e., be esterified with an alcohol. Such groups may be represented bythe general formula V—A⁴—R⁵—N^(⊕)(R⁶)₂—R⁷—V^(⊖)  V

-   -   in which A⁴ is a valence bond, —O—, —S— or —NH—, preferably —O—;    -   V is a carboxylate, sulphonate or phosphate diester        (monovalently charged) anion;    -   R⁴ is a valence bond (together with A⁴) or alkanediyl,        —C(O)alkylene- or —C(O)NHalkylene preferably alkanediyl, and        preferably containing from 1 to 6 carbon atoms in the alkanediyl        chain;    -   the groups R⁶ are the same or different and each is hydrogen or        alkyl of 1 to 4 carbon atoms or the groups R¹ together with the        nitrogen to which they are attached form a heterocyclic ring of        5 to 7 atoms; and

R⁷ is alkyanediyl of 1 to 20, preferably 1 to 10, more preferably 1 to 6carbon atoms.

One preferred sulphobetaine monomer has the formula VI

where the groups R¹⁵ are the same or different and each is hydrogen orC₁₋₄ alkyl and s is from 2 to 4.

Preferably the groups R⁸ are the same. It is also preferable that atleast one of the groups R⁸ is methyl, and more preferable that thegroups R⁸ are both methyl.

Preferably s is 2 or 3, more preferably 3.

Alternatively the zwitterionic group may be an amino acid moiety inwhich the alpha carbon atom (to which an amine group and the carboxylicacid group are attached) is joined through a linker group to thebackbone of the biocompatible polymer. Such groups may be represented bythe general formula VII

-   -   in which A⁵ is a valence bond, —O—, —S— or —NH—, preferably —O—,    -   R⁹ is a valence bond (optionally together with A⁵) or        alkanediyl, —C(O)alkylene- or —C(O)NHalkylene, preferably        alkenediyl and preferably containing from 1 to 6 carbon atoms;        and    -   the groups R¹⁰ are the same or different and each is hydrogen or        alkyl of 1 to 4 carbon atoms, preferably methyl, or two or three        of the groups R¹⁰, together with the nitrogen to which they are        attached, form a heterocyclic ring of from 5 to 7 atoms, or the        three group R¹⁰ together with the nitrogen atom to which they        are attached form a fused ring heterocyclic structure containing        from 5 to 7 atoms in each ring. The zwitterionic monomer and        hydrophobic comonomer are preferably used in the polymerisation        in weight ratios in the range 1:(1-10), preferably 1:(1.5-4).

The polymer produced in the process has the following general formulaVIII

in which n, m, R¹ and X are as defined in relation to the generalformula I, p is as defined in relation to general formula II, t is 1 andu is 1 to 10.

-   -   u is preferably in the range 1.5 to 5. Preferably t:u is        substantially the same as the mole ratio of monomers used in the        polymerisation process.

In the polymerisation process, the polymerisation solvent system isselected such that the zwitterionic monomer, which is generally highlyhydrophilic, and the hydrophobic comonomer co-dissolve, and so that thepolymer is retained in solution at the end of the polymerisation.Suitable solvents include lower alkanols including glycols, alkanoatesand admixtures of alcohols or ethers with esters such as loweralkyl-lower, as well as ethers including glycol ethers. Examples ofalcohols, which include glycols, are methanol, ethanol, propan-2-ol,propan-1-ol, and butanol. Examples of ethers are tetrahydrofuran anddiethylether. Examples of esters are ethyl, propan-1-yl, and propan-2-ylacetate. Often mixtures of solvents are used to form the polymerisationsolvent system. For example mixtures of alcohols and esters are found tobe convenient. Whilst esters alone tend not to be solvents for thepolymers their presence in minor amount in the product mixture improvesthe recover step. One particularly preferred combination is a majoramount of propan-2-ol and a minor amount of propan-2-yl acetate. Forinstance mixtures of alcohol to ester may be in the range 10:1 to 1.5:1by weight, most preferably in the range 5:1 to 2:1.

The polymerisation solvent system is made up of solvent added to thereaction vessel prior to addition of monomer, any solvent in which themonomers and/or initiator are dissolved and, if necessary, solvent addedthroughout the polymerisation in parallel with monomer addition, orafter the monomer feed phase is complete. The solvent in the reactionvessel prior to commencement of the monomer feed phase may be the sameas or different in composition to the solvent in the monomer solutions.Preferably it consists of the same components, in the same or adifferent ratio.

The monomers may be fed into the reaction vessel as a mixed solution orseparate solutions, one containing each of the monomers, may be fedsimultaneously to the reaction vessel. If the monomers are addedseparately, the two monomer solutions may be added at substantiallyconstant rates and consequently constant ratios of one monomer to theother or the ratio of the rates of addition may be adapted so as tomaintain a constant ratio of monomers in the polymerisation vessel. Itis most convenient, and good results are achieved, where the monomersare mixed together before being added to the polymerisation vessel.Generally a reservoir of the premixed monomer is generated and the mixedmonomer solution fed from that reservoir into the reaction vessel.Alternatively, separate solutions of the two monomers may be premixedimmediately before addition to the reaction vessel, such that the ratiosof the monomers may be controlled and changed throughout thepolymerisation process if desired.

Generally the monomer solution(s) when they are added to the reactionvessel are at ambient temperature. It is convenient for thepolymerisation mixture in the polymerisation vessel to be at a raisedtemperature, generally a constant temperature throughout thepolymerisation process. It is particularly convenient for the vessel tobe kept at reflux, to provide a substantially constant temperature. Thereaction vessel is generally at atmospheric pressure. The choice ofpolymerisation solvent system may further be dependent upon a suitablereflux temperature. Generally the reaction temperature is in the range45 to 120° C., most preferably in the range 60 to 100° C., for instancein the range 80 to 90° C.

The free radical initiator used in the polymerisation process ispreferably a thermal initiator. Provided the reaction temperature of theinitiator is higher than ambient, it is convenient for the initiator tobe co-dissolved into the or one of the monomer solutions. The initiatoris selected such that initiation takes place in the reaction vessel,usually at the temperature in the polymerisation vessel. A suitablethermal initiator is o-azo-isobutyronitrile (AIBN),bis(4-tert.butycyclohexyl)peroxydicarbonate or tert.butylperoxypivalate.Alternatively it is possible to use a redox initiation system, in whichone component of the system is present in the reaction vessel and theother is added simultaneously, for instance co-dissolved, with themonomer solution(s). The initiator is for instance used in a totalamount in the range 0.05 to 2%, preferably 0.1 to 1% by weight based onthe weight of monomers.

The polymerisation process is carried out under monomer starvedconditions. The prime determinant of the rate of polymerisation is therate at which the monomers are added. Thus the rate of consumption ofmonomers in the polymerisation vessel is substantially the same as therate of addition of monomers to the vessel. This results in the monomerratio remaining substantially constant throughout the monomer feedstage, at the end of which polymerisation is close to completion, forinstance at least 90% complete, for instance at least 95% complete asjudged by residual monomer. It is, nevertheless, preferred forpolymerisation to be continued for a period after monomer feed iscomplete. This results in reduction of residual monomer to very lowlevels.

The polymer product preferably has a molecular weight in the range20,000 to 10⁶, preferably 50,000 to 10⁶, more preferably in the range(1-5)×10⁵ D.

Following completion of polymerisation, polymer is recovered from theproduct mixture by steps including precipitation of the polymer into anon solvent precipitation liquid. It may be desirable for thepolymerisation solvent system to be removed in part or substantiallycompletely, from the product mixture before contact with theprecipitation liquid but it is generally found to be advantageous forthe product mixture to be directly mixed with the precipitation liquid.Where the polymerisation solvent system is evaporated completely, it isnecessary to redissolve the polymer prior to precipitation. A suitableprecipitating liquid is acetone.

Preferably the polymerisation solvent is retained in the precipitationstep since this optimises maintenance of copolymerised monomer and lowmolecular weight polymer in the liquid phase. Preferably the productmixture and precipitation liquid are added concurrently over the sameperiod to a recovery vessel. This process allows the maintenance of asubstantially constant ratio of precipitation liquid to polymerisationsolvent, which optimises the isolation process. To improve the isolationthe precipitation may be repeated after redissolution of the polymer ina suitable solvent. Preferably there is concurrent addition of thepolymer solution and precipitation liquid to a recovery vessel.

We generally find that the yield of the polymerisation reaction andrecovery stages is high, indeed at least as high as the prior artone-pot process, for instance more than 80 or 85% after twoprecipitations.

Th process of the invention results in production of polymers havingvery low compositional variation. The zwitterionic monomers andhydrophobic comonomer having different reactivity constants, willnormally polymerise at different rates. Furthermore, the monomers tendto react with growing polymer chains having end groups of the same typerather than a different type, thereby forming blocky copolymers. Thepolymers of the present invention tend to have a much lower compositionsvariation on a molecular and sub-molecular scale.

Physical and chemical characterisation of the copolymer formed by thepolymerisation process of the invention as compared to that produced bythe “one-pot” process of WO-A-93/01221, by spectroscopic analysis (NMR,IR, UV-visible) analysis, thermal analysis (DSC, TGA) and molecularweight determinations by gal permeation chromatography, do not allowdiscrimination of the two polymers. We have found, however, that thepolymers can be distinguished on the basis of solubility parameters inselected analytical polymer solvent systems.

Combination of a very hydrophilic monomer such as HEMA-PC, with ahydrophobic monomer such as dodecylmethacrylate will lead to anamphiphilic polymer with unusual solubility properties. Any solvent inwhich the polymer is to be dissolved, for instance for use in a coatingprocess, must be able to solvate both the zwitterionic head group andthe long alkyl chains. We have demonstrated by use of NMR that mixedsolvent systems using miscible solvents with different polarities allowsoptimum solvation of the polymer. Where the polymer is produced by theprior art one-pot process and is relatively blocky, the use of loweralkanols inadequately solvates the hydrophobic regions of the polymer.Using higher alkanols can solvate the prior art copolymers adequatelybut is disadvantageous in that solvent removal from the wet coatingrequires higher temperature and/or longer times or is difficult to driveto completion. Coating formation may be unsatisfactory due to highviscosity.

Our investigations have shown that the prior art copolymers form hazysolutions in lower alkanols such as methanol, ethanol and isopropanol.The haze is caused by a fine suspension of undissolved particulatematter which can be isolated and shown to consist polymer which containsa high ratio hydrophobic group to hydrophilic group. Whilst the use of asolvent system comprising a mixture of a chlorinated alkane and analcohol such as used in the prior art mentioned above may provideadequate salvation of the blocky copolymers of the prior art, the use ofchlorinated solvents is generally undesirable from an environmentalpoint of view. Also certain substrates may be adversely affected by suchsolvents.

The polymers made by the new polymerisation process of the invention canthus be understood to be different to those produced by the prior art.The examples below provide further data showing the difference betweenthe polymers. The novel polymers have particularly desirable propertiesfor coating a wide range of substrates. The present inventioncomprehends coating compositions comprising a solution of the novelpolymer in a coating solvent system. The coating solvent system maycomprise alcohols, esters or ethers and alkanes, and mixtures thereof.Binary mixtures of miscible solvents may be used such as of an alcoholand an alkane, or an alcohol and water. Alcohols include C₁₋₁₀-alkanols,especially methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol,butan-2-ol, hexanol and octanol. Alkanes include C₅₋₈-alkanes, which maybe straight chain, branched or cyclic, for instance n-pentane, n-hexane,n-heptane and cyclohexane. Mixtures of solvents may be in a ratio of10:1 to 1:10, for instance in the range 5:1 to 1:5 by volume.

In a second aspect of the invention, there are provided novel solutionsof copolymers of a zwitterionic monomer of the general formula I and ahydrophobic comonomer of the general formula II in ratios (based onmonomer) in the range 1:(1-5), (1.5-3) and having a propan-2-ol (IPA):water solubility characteristic such that the polymer is substantiallyinsoluble in mixtures of 0-5% IPA, substantially wholly soluble at 20 to40% IPA and at 100% IPA, and substantially insoluble at 60-90% IPA, thecopolymer in the novel solution being at a concentration in the range 1to 200 mg/ml in a solvent system comprising a mixture of miscibleliquids each having a vapour pressure of at least 1 kPa at 25C thesolution having a turbidity of less than 50 NTU.

Solubility in this aspect of the invention is determined by a turbiditytest in which a 20 mg/ml solution is tested in a Genway Turbidimeter 605and the turbidity recorded. Turbidity of the novel solution is alsotested in this device.

A polymer having the above solubility characteristics will be suitablefor coating substrates subsequently to be used in aqueous environments,to provide adequate coating stability on the substrate. The copolymers,being substantially wholly soluble in the range 20-40% volume IPA is aresult of low blockiness, improved random distribution of monomers inthe polymer. The copolymers also tend to be substantially wholly solublein 100% IPA, possibly due to a particular conformation of polymer in asubstantially non-hydrated form. In the intervening IPA contents, in therange 60-90%, the polymer is insoluble.

In this aspect of the invention the zwitterionic monomer is preferablyselected from monomers of the formula I in which m is 0, n is 2, and xis a group of formula III, preferably in which A² and A³ are —O— and Wis —W¹ NR² ₃. More preferably x is a group of formula IV. In thehydrophobic comonomer, p is preferably 4 to 18, more preferably 8 to 16and C_(p)H_(2p+1) is straight main.

The copolymer in the novel solution defined by the solubilitycharacteristics in the isopropanol:water mixed solvent system, hasparticularly desirable coating characteristics. The copolymers, whencoated from a coating solvent system in which they are wholly dissolved,provide smooth uniform coatings with extremely good biocompatibilityperformance.

Whilst the coating composition may comprise other solvent systems, it ispreferred that they consist of water:alcohol mixtures. The alcohol maybe methanol, but is preferably a C₂₋₄-alcohol, more preferably selectedfrom ethanol and isopropanol. The solvent system preferably is a mixtureof water and isopropanol in a proportion at which the copolymer issubstantially wholly soluble, and at a concentration in which thepolymer is fully dissolved. Preferably the concentration of thecopolymer in the coating composition is in the range 1-200 mg/ml, mostpreferably in the range 5-50 mg/ml, for instance 10-20 mg/ml. Preferablythe ratio of alcohol:water is in the range (99-1): 1, more preferably(20-3):1.

We have found that, by using the novel copolymers, it is possible toprovide water alcohol solutions with high water contents, for instanceat least 50%, most preferably at least 80% water by volume. The polymersare nevertheless found to be stably adherent when coated ontohydrophobic substrates which are then used in aqueous environments. Thesolutions with high water contents are found to be particularly usefulfor coating substrates which would be harmed by higher concentrations ofalcohol or by other organic solvent systems. Such substrates, which aresensitive to coating systems include membranes, and other poroussubstrates.

In a third aspect of the invention, there is provided anaqueous/alcoholic solution of a copolymer of a zwitterionic monomer ofthe formula I and a hydrophobic comonomer of the formula II at a molarratio in the range 1:(1.5 to 10) in a solvent consisting of a mixture ofan alcohol and water in a volume ratio in the range 10:1 to 1:5, thealcohol and its level being selected such that a 20 mg/ml solution ofthe polymer has a turbidity of less than 50 NTU.

The solution itself preferably has a turbidity value less than 50 NTU,preferably less than 20 NTU.

The alcohol may be a glycol or a polyol, but is preferably a monobasicalcohol. The alcohol preferably has a vapour pressure at 25C of at least0.1, preferably at least 1.0, for instance at least 2.0 up to 20 Pa,preferably in the range 5 to 20 kPa. Suitable alcohols are methanol,ethanol, propan-1-ol, propan-2-ol, butan-1 , butan-2-ol,methyl-1-propanol, methyl-2-propanol, pentan-2-ol, pentan-1-ol,hexan-1-ol and hexan-2-ol. Particularly preferred is propan-2-ol (vapourpressure 6.02 kPa at 25C).

In a fourth aspect of the invention, there is provided a coatingsolution of a copolymer formed from zwitterionic monomer of the generalformula I and hydrophobic comonomer of the general formula II in molarratios in the range 1:(1-10) in a coating solvent system comprising amixture of a C₅₋₁₀-alkane and a C₁₋₁₀-alkanol in a volume ratio in therange 1:(0.1-10).

Suitable ratios of the alkane and alcohol are 1:5 to 5:1.

The aqueous-alcoholic solution and the coating solution are preferablysubstantially clear, that is have a turbidity value, of less than 50NTU's. The solutions preferably have a polymer concentration in therange 1-200 mg/ml, preferably in the range 5-50 mg/ml, for instance inthe range 10-20 mg/ml, in the solvent system.

The coating composition is used in a novel coating process in which asubstrate is coated with the solution, and the solvent is removed fromthe coating by evaporation to leave a polymer coated surface.

Suitable alkanes are C₅₋₈-branched, straight or cyclic alkanes,especially C₆₋₈-alkanes, for instance n-hexane, n-heptane andcyclohexane. The alcohol is selected so as to be wholly miscible withthe alkane. Suitable alcohols are mentioned above in connection with thethird aspect and are preferably selected from ethanol and isopropanol.

In the third and fourth aspect of the invention the polymer ispreferably formed from preferred monomers as specified in connectionwith the second aspect of the invention. Preferably the monomer ratiosare selected such that the polymer is insoluble in water (100%).

The novel solutions of the second, third or fourth aspect of theinvention may be used in a novel coating process. In the coatingprocess, removal of the is solvent may be conducted under application ofheat and/or reduced pressure. The conditions are selected so as tominimise damage to the polymer and/or the substrate, to optimise thesmoothness of the coating and to avoid high temperatures whereinflammable solvent is present.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings

FIGS. 1 and 2 show the results of Example 3;

FIGS. 3 a and 3 b, 4 and 5 show the results of Example 4; and

FIG. 6 shows the results of Example 5 below.

The following examples illustrate the invention.

EXAMPLE 1

Preparation of (2-methacryloyloxyethyl-2′-trimethylammoniumethylphosphate, inner Salt)-co-(n-dodecyl methacrylate) 1:2 copolymer

The zwitterionic monomer (48 g, 0.163 mole) (HEMA-PC) was weighed in aglove box environment dried by P₂O₅. Dodecylmethacrylate(laurylmethacrylate, LM) (82.8 g, 0.326 mole), andα-azo-isobutyronitrile (AIBN) initiator (0.2 g, 0.15%) were weighed inair. A 3 neck reaction flask, fitted with water condenser, nitrogen gasflow and monomer feed tubing, and primed with anhydrous isopropanol(isopropyl alcohol, IPA) (120 g) and isopropylacetate (40 g) solvent,was immersed in a heated 90° C. oil bath so that the solvent system isrefluxing at a temperature of about 83° C. The monomers and initiatorwere dissolved in isopropanol (108 g) isopropylacetate (56 g) solventand magnetically stirred in a measuring cylinder sealed with parafilm.The reaction mixture was drawn into polypropylene tubing placed insidethe measuring cylinder and through silicone tubing via a peristalticpump to enter the heated reaction vessel in a dropwise process. Acomplete transfer to the heated vessel took 2 hours. The reaction wasstirred for another hour. A second charge of AIBN initiator (0.4 g),dissolved in isopropylacetate (6 g), was added and the reaction mixturewas stirred for a further 2 hours, taking the total reaction time to 5hours.

Once cooled to 40-60° C. temperature, the reaction mixture was pumpedthrough a sintered glass filter and dropwise precipitated into 400 mlacetone and 40 ml isopropanol. Concurrently 2800 ml acetone was alsopumped in over 1 hour. A white solid product settled from the acetoneleaving a slightly cloudy supernatant. The supernatant was removed andthe white solid is redissolved in 200 ml isopropanol. The precipitationis repeated using the same volumes and solvents and method of mixing.The product was separated by Buchner flask and 113 Whatman wetstrengthened filter paper, and dried in a room temperature vacuum ovenfor up to 24 hours. The product was weighed (98 g) to provide a 75 wt %yield, bottled in a brown glass vial and refrigerated. The molecularweight was determined by gel permeation chromatography (GPC) using aWaters 717 Autosampler, a Waters 510 pump, an Asahipak GS<700 column anda Viscotek T60 light scattering detector and was found to be in therange (2-6)×10⁵ D.

EXAMPLE 2

Copolymer Ratios 1:1 and 1:4

Using the polymerisation method of example 1, copolymers of the samezwitterionic monomer and hydrophobic comonomer were synthesised at molarratios 1:1 and 1:4. Apart from the use of the different monomer ratios,the reaction conditions were identical were the solvents the same.

EXAMPLE 3

Solubility of Products of Monomer-Starved vs One-Pot Polymerisation

The copolymers produced in examples 1 and 2 and a one-pot copolymer ofHEMA-PC and dodecylmethacrylate 1:2 made according to example 1 ofWO-A-93/01221 in isopropanol:ethyl acetate 43:17, were subjected tocomparative solubility tests. The polymers were dissolved, at aconcentration of 20 mg/ml in various isopropanol:water mixtures,differing by their isopropanol-water composition. Briefly, the polymerswere added to 100% alcohol. The appropriate amount of water was added togive the desired ratio of alcohol to water, and the mixture was shaken.If there was no precipitation the solution was then tested for itsturbidity, in a Genway Turbidimeter device. The turbidity is recorded inNTU's.

The results are shown in accompanying FIGS. 1 and 2. Whilst the graphshows values of up to 200 NTU, in fact the polymers having turbidityindicated as 200 NTU are insoluble and this value is chosen as anarbitrary value. The turbidity values determined in the Turbidimeter maynot be precisely 200 NTU. FIG. 1 shows the difference in the solubilitycharacteristics between the one-pot, comparison copolymer and thepolymers of the invention formed in the monomer starved polymerisationprocess. The comparison polymer is insoluble in all ratios ofwater:isopropanol. The copolymer of the invention, by contrast, has a“window of clarity” for isopropanol contents in the range 20 to 40% byvolume.

FIG. 2 shows that copolymers produced by the monomer starved process ofthe invention with high levels of hydrophobic comonomer may besubstantially insoluble at all concentrations of water, though solublein 100% isopropanol. For copolymers with high levels of the zwitterionicmonomer, for instance 50 mole %, the polymers tend to be soluble at alllevels of IPA less than 55 or 57% by volume and even in 100% water. Suchcopolymers would tend to be insufficiently stable on substrates for usein aqueous environments. The copolymer formed of a 1:2 mixture ofzwitterionic monomer:hydrophobic comonomer, however, has a window ofclarity at isopropanol contents in the range 20-40%, being insoluble inwater and low water content mixtures. Such copolymers give adequatecoating stability on hydrophobic substrates.

EXAMPLE 4

Monitoring of Residual Monomer in Monomer-Starved and One-Dot Method

The one-pot method and monomer starved method of polymerisation for the1:2 polymers of example 3 were monitored throughout their progress forresidual monomer and reported as a percentage of the total monomer whichhad been added into the polymerisation mixture at the relevant time. Theresults are shown in FIGS. 3 a and 3 b, respectively. These plots havebeen combined and FIG. 4 shows the percentages of the individualmonomers remaining as a function of time. A logarithmic scale is usedfor time, but it will be appreciated that the monomer feed process isfar quicker, and has substantially the same yield. In the graphs, theHEMA-PC monomer is referred to as MPC.

The results have also been replotted in FIG. 5 to show the % residual LMmonomer against the % residual HEMA-PC (MPC) monomer at each time point.This indicates that the plot for the monomer-feed tends to a straightline with the intercept on the LM axis being close to the origin. Thebest straight line through the points represented by

-   -   y=a x+b where y is % residual LM, and        -   x is % residual MPC,    -   for the invention should have a is in the range 0.9 to 1.1, and        -   b is in the range −10 to 10

In the example the equation is y=0.98x+3.3. The coefficient ofcorrelation is over 0.97. Ideally the relationship would be y=x. Acomparison of the one-pot results indicates that these do not have adirect correlation but rather % LM residual is always higher thanresidual HEMA-PC, often by more than 10%. Thus the monomer feed processmeets the requirement of the claim that the mole ratio of the twomonomers does not vary throughout the polymerisation by more than 10%,whereas the one-pot method does not satisfy that test.

The results show the residual monomer ratio is substantially constantthroughout the polymerisation process in the invention, whereas in theone-pot method one monomer is removed into polymer at a far greater ratethan the other, resulting in uneven polymer composition. Polymers formedearly on in the progress of the application will have a differentcomposition than those formed late.

EXAMPLE 5

Solutions in Alcohol/Water Mixtures of Novel Copolymer

The copolymer produced in Example 1 was dissolved in mixtures of threedifferent alcohols and water, each at alcohol/water contents in therange 100/0-0/100. The alcohols were methanol (MeOH), ethanol (EtOH) andisopropanol (IPA). The turbidity of the solutions is determined in thesame manner as in Example 3.

The results are shown in accompanying FIG. 4.

FIG. 4 indicates that the novel copolymer of the invention has a windowof clarity for both isopropanol and ethanol mixtures, though at slightlydifferent alcohol/water levels.

EXAMPLE 6

Coating Performance of 100% Alcohol Solutions of Products of MonomerStarved vs One-Dot Polymerisation

The polymer made according to the process of example 1 and the prior art1:2 copolymer were each dissolved in 100% methanol, ethanol andisopropanol and coated onto substrates for roughness testing. Thesubstrate was glass coverships. It was prepared by sonication indichloromethane for 10 min. The solutions were 20 mg/ml and were coatedby dip-coating and removed at about 3 mm/s, dried at room temperaturefor 24 hours.

Roughness determinations were carried out by atomic force microscopy in“tapping mode” (trademark) (Digital Instruments, AFM Dimension 3000model with a Nanoscope III a control unit). The results are shown intable 1 below.

TABLE 1 Comparative Inv ntion Alcohol Rq Ra Rq Ra MeOH 25.8 16.7 0.5 0.4EtOH 67.1 49.6 5.4 4   IPA  3.4  2.6 2.2 1.7

EXAMPLE 7

Coating Performance of Novel Copolymer Solutions in Alcohol/WaterMixtures Compared to 100% Alcohol

The polymer produced according to Example 1 is used to provide coatingsusing the coating process described generally in example 5, from 100%ethanol and isopropanol and from 20:80 alcohol:water (by volume)mixtures. The coatings were subjected to the roughness test of Example6. The results are shown in the accompanying table.

TABLE 2 Solvent System Rq Ra EtOH 5.4  4   EtOH (20%): H₂O (80%) 0.880.69 IPA 2.2  1.7  IPA (20%): H₂O (80%) 0.93 0.66

EXAMPLE 8

Surface Wettability

The polymer produced according to Example 1 and the prior art copolymerdescribed in Example 3 were dissolved (at 10 g/l) in a range of solventssystems and coated onto precleaned glass coverslips using the generaltechnique described in Example 6. The coated substrates were subjectedto surface wettability testing by determining their static contactangles for a water droplet. The results are shown in Table 3.

TABLE 3 Static Contact Angle Polymer Solvent System Mean (θ) S.D.Invention MeOH 45.0 4.3 Invention EtOH 56.5 3.8 Invention IPA 77.9 14.1 Invention BuOH 104.3  1.9 Invention 60:40 H₂O:IPA 36.0 3.5 Invention80:20 H₂O:IPA 31.3 3.8 Invention 99:1 Hexane:EtOH 107.3  6.3 Invention50:50 Hexane:EtOH 61.0 5.1 Comparative MeOH 59.0 5.1 Comparative EtOH83.2 5.6 Comparative IPA 62.0 8.2 Comparative BuOH 100.5  7.6 BuOH isn-butanol

There was a suggestion of a trend to increasing contact angle as thelength of the alkyl component of the alcohol increased. Results from theaqueous alcohol solutions were encouraging, showing a significantlylower static contact angle than for the single-solvent alcohol systems.

EXAMPLE 9

Coating of Blood Filtration Material

A leucocyte filter manufactured by Pall Corp. and comprising a fabricformed of microfine polyethylene teraphthalate fibres was coated bybeing dipped into 500 ml 5 g/l solutions of the polymer of Example 1 ina 70:30 water IPA mixture and in neat IPA. The filter materials weredried for several hours. The coated filters were tested for the criticalwetting surface tension (CWST) by placing single drops of a series ofstandard solutions having known surface tension and observing whetherthe drops completely wet the surface. The surface energy was reported asthe mean of the surface tensions of the solution having the highestsurface tension which does not wet and the solution having the lowestsurface tension which does wet the filler. The results are compared tothe uncoated filter tested in the same way as compared to the uncoatedfilter. The CWST of the uncoated filter was 50 dynes/cm, the filtercoated with a polymer coated from neat IPA was increased to 58 dynes/cmand the filter coated from the aqueous alcohol solution was increased to65 dynes/cm.

Furthermore the coated filters were contacted with drops of one of thetest solutions, which had a tension of 56.5 dynes/cm and the averagetime taken for the solution to soak into the filter. The filter coatedfrom the aqueous alcohol solution absorbed the solution in about onethird the time of the filter coated from the neat IPA solution.

Upon contact of the coated filters with blood both coated filters hadadequate resistance to thrombus formation and cell deposition determinedafter contact with blood, and using scanning electron microscopy toobserve the blood contacted surface.

EXAMPLE 10

Solutions in Alcohol:Alkane Mixtures

The polymer produced as in Example 1 and the comparison polymer formedby the one-pot method referred to in Example 3 were tested for theirdissolution characteristics in hexane:alcohol mixtures, at a polymerconcentration of 10 g/l. The alcohols used were ethanol and isopropanol.It was found that, for the novel polymer, 1.2% ethanol or 4.6%isopropanol was needed to dissolve the polymer completely (produce avisually clear solution). For the prior art polymer 2.2% ethanol or 6.3%isopropanol was needed. These differences are significant, and the loweralcohol level is expected to have advantages where a substrate to becoated is, for instance, a polyurethane.

EXAMPLE 11

Effect of Changing Length of Alkyl Chain in Comonomer

Example 1 was repeated, by using, in place of dodecyl methacrylate, thesame weight of other alkyl methacrylates. 0.1 g of the polymers producedwere then dissolved to form a 3 ml solution in alcohol, the alcohol andchain length of the alkyl being as specified in Table 4. To thealcoholic polymer solutions water was added with shaking and the aqueousalcoholic solutions observed to determine whether cloudiness appearedimmediately upon addition of a small volume of water. If so, more waterwas added up to a total volume of about 10 ml, to determine whether thecloudiness dissipated, that is whether the polymers exhibited a windowof clarity at some water alcohol ratios. In Table 4, a tick (✓) meansthat a window of clarity is exhibited, and a dash (-) means the polymeris soluble at all water:alcohol ratios tested. The tick in parenthesesmeans the cloudiness dissipated only upon warming the 10 ml solution.

TABLE 4 Alkyl Chain Length in Comonomer Alcohol C1 C2 C4 C6 C8 C12 C16MeOH — — — — — — — EtOH — — — — — ✓ ✓ n-ProH ✓ — — ✓ ✓ ✓ ✓ IPA (✓) ✓ — ✓✓ ✓ ✓

EXAMPLE 12

Changing Ratio of Monomers

The polymerisation process of Example 1 was repeated but using a 2:1,1:1 and 1:4 mole ratio of zwitterionic monomer (HEMA-PC) to hydrophiliccomonomer (LM). The 2:1 and 1:1 copolymers are relatively water-solubleand so do not form stable coatings on surfaces to be used in aqueousenvironments. The polymers did exhibit similar characteristics as the1:2 copolymer in terms of being soluble in neat isopropanol. The 2:1 and1:1 and 1:2 copolymers were soluble in methanol and addition of water tothe methanol solutions did not make them cloudy. Upon addition of waterto the 1:4 copolymer solution in ethanol, isopropanol and n-propanolprecipitated the polymer, the precipitation being irreversible even uponadding further water. The polymer solvent combination shows no windowsimilar to that, illustrated in FIG. 1. For the 2:1, 1:1 and 1:2copolymers addition of water to the methanolic solutions did not turnthe solutions cloudy. For solutions of those three polymers in ethanol,isopropanol and n-propanol, addition of water initially results incloudiness, but this cloudiness dissipates upon increasing the amount ofwater.

If the dodecyl methacrylate is replaced by n-butyl methacrylate at thesame weight ratios different solubility characteristics are exhibited ascompared to the dodecyl methacrylate derived analogues, which may be aconsequence of the fact that those polymers are likely to have a greaterdegree of blockiness -comprising longer blocks of alkylmethacrylate-derived units, due to the higher mole content ofbutylmethacrylate monomer in the mixture as compared tododecylmethacrylate.

1. A polymerisation process conducted in a reaction vessel in whichethylenically unsaturated monomers consisting substantially only of: a)1 part by mole zwitterionic monomer of the general formula I

in which n is 2 to 24; m is 0 to 20; of the groups R¹, one may be methylor hydrogen and the rest are all hydrogen; and X is a zwitterionicgroup; and b) 1 to 10 parts by mole hydrophobic comonomer of the generalformula II

in which p is 1 to 24; are copolymerised in solution in a solvent systemin which the monomer mixture and the polymer are soluble and whichcomprises at least one solvent; comprising the steps: adding said atleast one solvent to the reaction vessel; adding a radical initiator tothe reaction vessel; feeding the monomers constantly over a monomer feedphase into the reaction vessel under conditions at which polymerisationtakes place, at a predetermined monomer feed rate whereby the molarratio of zwitterionic monomer to hydrophobic comonomer in the reactionvessel is maintained substantially constant (±10%) throughout themonomer feed phase; and polymerising the monomers to producezwitterionic polymer product.
 2. A process according to claim 1 in whichm is 0, and n is in the range 2 to
 4. 3. A polymerisation processaccording to claim 2 in which n is
 2. 4. A process according to claim 1in which p is at least
 4. 5. A polymerisation process according to claim4 in which p is in the range 6 to
 18. 6. A polymerisation processaccording to claim 5 in which p is
 12. 7. A process according to claim 1in which C_(p)H_(2p+1) is a straight chain group (CH₂)_(p)H.
 8. Aprocess according to claim 1 in which X has the general formula III

in which the moieties A² and A³ which are the same or different, areselected from the group consisting of —O—, —S—, —NH— and a valence bond;and W⁺ is a group comprising an ammonium, phosphonium or sulphoniumcationic group and a group linking the anionic and cationic moietieswhich is a C₁₋₁₂-alkanediyl group.
 9. A polymerisation process accordingto claim 8 in which W⁺ is a group of formulaW¹—N⁺R² ₂₃, —W¹—P⁺R³ ₃, —W¹—S⁺R³ ₂ or —W¹-Het⁺ in which: W¹ is selectedfrom the group consisting of alkanediyl of 1 to 6 carbon atomsoptionally containing one or more ethylenically unsaturated double ortriple bonds, arylene, alkylene arylene, arylene alkylene, alkylene arylalkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene andalkylene cycloalkyl alkylene, which group W¹ optionally contains one ormore fluorine substituents and/or one or more functional groups; andeither the groups R² are the same or different and each is selected fromthe group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, andaryl, or two of the groups R² together with the nitrogen atom to whichthey are attached form an aliphatic heterocyclic ring containing from 5to 7 atoms, or the three groups R² together with the nitrogen atom towhich they are attached form a fused ring structure containing from 5 to7 atoms in each ring, and optionally one or more of the groups R² issubstituted by a hydrophilic functional group; the groups R³ are thesame or different and each is R² or a group OR², where R² is as definedabove; and Het is an aromatic nitrogen-, phosphorus- orsulphur-containing ring.
 10. A process according to claim 8 in which Xhas the general formula IV:

where the groups R⁴ are the same or different and each is hydrogen orC₁₋₄ alkyl, and q is in the range of from 1 to
 4. 11. A polymerisationprocess according to claim 10 in which each R⁴ is methyl.
 12. A processaccording to claim 1 in which the solvent system comprises a mixture ofan alcohol and an ester.
 13. A polymerisation process according to claim12 in which the alcohol is propan-2-ol and the ester is propan-2-ylacetate.
 14. A process according to claim 1 in which one solutioncontaining both of the monomers is fed to the reaction vessel.
 15. Aprocess according to claim 1 in which the contents of the reactionvessel are at a raised temperature compared to the monomers prior tobeing fed to the vessel during said monomer feed phase.
 16. A processaccording to claim 1 in which initiator is fed to the polymerisationvessel throughout the monomer feed phase, such that the ratio of monomerto initiator remains substantially constant throughout substantially theentire monomer feed phase.
 17. A process according to claim 1 in whichzwitterionic polymer product is recovered by i) mixing the productmixture with a precipitation liquid which is a non-solvent for thepolymer to produce precipitated polymer and ii) separating precipitatedpolymer from dissolved by-products in product solvent.
 18. Apolymerisation process according to claim 17 in which the mixing andseparating are conducted substantially without prior removal from theproduct mixture of any polymerisation solvent.
 19. A process accordingto claim 17 in which said mixing is carried out by concurrent additionof the product mixture and the precipitation liquid to a recovery vesselover a period of time.
 20. A process according to claim 17 in which theseparated precipitated polymer is redissolved in a solvent comprisingselected from the group consists of C₁₋₄-alcohols, mixtures of C₁₋₄alcohols, mixtures of a C₁₋₄ alcohol with a miscible C₅₋₁₂-alkane andmixtures of a C₁₋₄ alcohol and water.
 21. A process according to claim 1in which the product polymer has an average molecular weight (Mn) in therange (2×10⁴) to 10⁶.
 22. A solution of a copolymer formed of a) 1 partby mole zwitterionic monomer of the general formula I

in which n is 2 to 24; m is 0 to 20; of the groups R¹, one may be methylor hydrogen and the rest are all hydrogen; and X is a zwitterionicgroup; and b) 1.5 to 3 parts by mole hydrophobic comonomer of thegeneral formula II

in which p is 1 to 24; said copolymer having a propan-2-ol:watersolubility characteristic such that the copolymer is substantiallyinsoluble in mixtures of 0-5% propan-2-ol/100-95% water, substantiallywholly soluble at 20-40% propan-2-ol/40-60% water and at 100%propan-2-ol and substantially insoluble at 60-90% propan-2-ol/40-10%water, said solution comprising copolymer at a concentration in therange 1-200 mg/ml and a solvent system comprising a mixture of miscibleliquids each having a vapour pressure of at least 0.1 kPa at 25° C.,wherein the solution has a turbidity of less than 50 NTU, and thesolution consists essentially of said copolymer and the solvent system.23. A solution according to claim 22 in which the solvent systemcomprises a mixture of an alcohol and water.
 24. A solution according toclaim 23 wherein the alcohol is a C₁₋₁₀ to alkanol.
 25. A solutionaccording to claim 24 in which the alcohol is ethanol or propan-2-ol.26. A solution according to claim 22 in which m is 0, n is in the rangeof from 2 to 4, p is in the range 8 to 16, and X has the general formulaIV:

where the groups R⁴ are the same or different and each is hydrogen orC₁₋₄ alkyl, and q is in the range of from 1 to
 4. 27. A solutionaccording to claim 22 in which the copolymer is water insoluble.
 28. Anaqueous-alcoholic solution of a copolymer formed from a) 1 part by moleof zwitterionic monomer of the general formula I

in which n is 2 to 24; m is 0 to 20; of the groups R¹, one may be methylor hydrogen and the rest are all hydrogen; and X is a zwitterionicgroup; and b) 1.5 to 10 parts by mole of a hydrophobic comonomer of thegeneral formula II

in which p is 1 to 24; dissolved in a solvent system consisting of amixture of an alcohol and water in a volume ratio in the range 10:1 to1:5, the alcohol and its level being selected such that a 20 mg/mlsolution of the copolymer has a turbidity of less than 50 NTU.
 29. Anaqueous-alcoholic solution according to claim 28 which has a turbidityvalue less than 20 NTU.
 30. An aqueous-alcoholic solution according toclaim 28 in which the alcohol is a C₁₋₁₀ alkanol.
 31. Anaqueous-alcoholic solution according to claim 30 in which the alcohol ispropan-2-ol.
 32. An aqueous-alcoholic solution according to claim 28 inwhich the proportion of water in the solvent system is at least 50%. 33.An aqueous alcoholic solution according to claim 28 in which m is 0, nis in the range of from 2 to 4, p is in the range 8 to 16, and X has thegeneral formula IV:

where the groups R⁴ are the same or different and each is hydrogen orC₁₋₄ alkyl, and q is in the range of from 1 to
 4. 34. A coating solutioncomprising a copolymer formed from a) 1 part by mole of a zwitterionicmonomer of the general formula I

in which n is 2 to 24; m is 0 to 20; of the groups R¹, one may be methylor hydrogen and the rest are all hydrogen; and X is a zwitterionicgroup; and b) 1-10 parts by mole of a hydrophobic comonomer of thegeneral formula II

in which p is 1 to 24; in molar ratios in the range 1:(1-10) in acoating solvent system comprising a mixture of a C₅₋₁₀-alkane and aC₁₋₁₀-alkanol in a volume ratio in the range 1:(0.1 to 10).
 35. Acoating solution according to claim 34 in which the alkane and alkanolare provided in ratios in the range (1-5):(5-1).
 36. A coating solutionaccording to claim 34 in which m is 0, n is in the range of from 2 to 4,p is in the range 8 to 16, and X has the general formula IV:

where the groups R⁴ are the same or different and each is hydrogen orC₁₋₄ alkyl, and q is in the range of from 1 to
 4. 37. A coating solutionaccording to claim 34 in which the alkane is selected from the groupconsisting of cyclohexane, n-hexane and n-heptane.
 38. A coatingsolution according to claim 34 in which the alkanol is selected from thegroup consisting of methanol, ethanol, propan-1-ol, propan-2-ol,butan-1-ol, butan-2-ol, methyl-1-propanol, methyl-2-propanol,pentan-2-ol, pentan-1-ol, hexan-1-ol and hexan-2-ol.
 39. A coatingsolution according to claim 34 in which the copolymer iswater-insoluble.
 40. A coating process comprising i) coating onto asubstrate a coating solution comprising a copolymer formed from a) 1part by mole of a zwitterionic monomer of the general formula I

in which n is 2 to 24; m is 0 to 20; of the groups R¹, one may be methylor hydrogen and the rest are all hydrogen; and X is a zwitterionicgroup; and b) 1-10 parts by mole of a hydrophobic comonomer of thegeneral formula II

in which p is 1 to 24; in molar ratios in the range 1:(1-10) in acoating solvent system comprising a mixture of a C₅₋₁₀-alkane and aC₁₋₁₀-alkanol in a volume ratio in the range 1:(0.1 to 10); and ii)removing said C₅₋₁₀ alkane and said C₁₋₁₀ alkanol.
 41. A coating processaccording to claim 40 in which said removing is conducted under reducedpressure.
 42. A coating process according to claim 40 in which saidremoving is conducted under raised temperature.